Design and Synthesis of Potent Retinoid X Receptor Selective Ligands That Induce Apoptosis in Leukemia Cells

Boehm, Marcus F.; Zhang, Lutao; Zhi, Lin; McClurg, Michael; Berger, E.; Wagoner, Murriel A.; Mais, Dale E.; Suto, Carla; Davies, Julia A.; Heyman, Rich

doi:10.1021/jm00016a018

Cited by 315 publications

(236 citation statements)

References 28 publications

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“…Drugs CDDO-Im, LG100268, and vorinostat were synthesized as previously described (21)(22)(23)(24), and LG101506 was synthesized by J-Star Research. Carboplatin and paclitaxel (C/P) were provided by the Drug Synthesis and Chemistry Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis of the NCI.…”

Section: Methodsmentioning

confidence: 99%

The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice

Cao

Royce

Risingsong

et al. 2016

Cancer Prevention Research

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LG101506 was originally synthesized to overcome some of the undesirable side effects of rexinoids. We compared the anticarcinogenic action of LG101506 and LG100268 and for the first time showed that both drugs are useful for prevention of lung cancer in A/J mice. These molecules markedly reduced tumor number, tumor size, and total tumor burden, when chronically administered to A/J mice that had been initiated with the mutagenic carcinogen, vinyl carbamate. Moreover, LG100268 synergized with the histone deacetylase inhibitor, vorinostat, for prevention of experimental lung cancer and enhanced the effect of carboplatin/paclitaxel for treatment of experimental lung cancer. Both rexinoids diminished the percentage of high-grade, highly malignant adenocarcinomas found at autopsy. In cell culture studies, the rexinoids exhibited potent anti-inflammatory properties at nanoMolar concentrations. These drugs suppressed the ability of lipopolysaccharide to stimulate the synthesis and secretion of nitric oxide and inflammatory cytokines and chemokines, such as IL6, IL1b, CXCL2, and CSF3, in macrophage-like RAW264.7 cells. The present results suggest that LG100268, LG101506, or a related rexinoid may have useful clinical applications in the field of oncology. Cancer Prev Res; 9(1);

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Section: Methodsmentioning

confidence: 99%

The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice

Cao

Royce

Risingsong

et al. 2016

Cancer Prevention Research

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“…Retinoid acid (RA) and its synthetic analogs exert their biological affects through two families of nuclear receptors: RA receptors (RAR a, b, g) and retinoid X receptors (RXR a, b, g), which are ligand-dependent transcription factors of the steroid/thyroid hormone nuclear receptor superfamily (Chambon, 1994;Boehm et al, 1995). Activated RARs bind to retinoic acidresponsive elements (RAREs) in the promotors of genes & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $25.00 www.nature.com/onc ONCOGENOMICS and thus regulate gene expression (Evans, 1988;Mangelsdorf et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Methylation of the retinoid response gene TIG1 in prostate cancer correlates with methylation of the retinoic acid receptor beta gene

2003

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Methylation of CpG islands and associated gene silencing may lead to malignant progression, but the mechanisms of CpG island methylation in cancer are unknown. The tazarotene-induced gene 1 (TIG1), also known as retinoid acid (RA) receptor-responsive 1 gene was first identified as an RA-responsive gene and was shown to be downregulated in prostate cancer. Here, we show that this downregulation is caused by the methylation of the promoter and CpG island of TIG1. TIG1 was methylated in 26 of 50 (52%) primary prostate cancers, but was not methylated in normal tissues or benign hyperplasias. Three of four tumors that metastasized, five of six that were poorly differentiated and all that were assigned a Gleason score higher than 8 (7/7) were methylated in the promoter of TIG1. The samples with peripheral invasion were more frequently methylated (21/32, 66%) than tissues without peripheral invasion (5/18, 28%). In addition, Gleason 7-10 cancers (21/30, 70%) were significantly more frequently methylated compared with Gleason 4-6 cancers (4/18, 22%) (Po0.01). The retinoic acid receptor beta (RAR-beta) gene was frequently methylated as well (42/50, 84%). When TIG1 showed methylation, RAR-beta was also methylated (25/26 samples). In almost all samples where RAR-beta was not methylated, TIG1 was also in an unmethylated state (14/15 samples). The methylation of TIG1 and RAR-beta was positively correlated (r ¼ 0.35; P ¼ 0.017). It is possible that the methylation of the retinoid response gene TIG1 occurred in response to the methylation and inactivation of RAR-beta. These observations may contribute to our understanding of mechanistic events leading to CpG island methylation in cancer.

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“…47 The ability of tTG to play an effector role in the apoptotic program depends on the cellular context. 48 In our RPMI 8226 cells as in HL-60 leukemia cells, both tTG expression and apoptosis are induced following RA treatment, 13,42 whereas in other cellular models, like NB-4 human acute promyelocytic leukemia cells, RA-dependent tTG induction may be observed without any occurrence of apoptosis. 49 tTG regulation in apoptosis probably requires cooperation with other effector agents, which may be differentially expressed and controlled according to the cell type studied.…”

Section: Discussionmentioning

confidence: 87%

“…41 Conflicting data have been reported about the type of RA receptors involved in this control. 14,42 Whereas a retinoid response element has been identified within the mouse tTG gene promoter, 43 such a responsive element has not yet been found in the human promoter sequence. 44 Moreover no negative glucocorticoid element has been identified in this promoter to date, and the mechanism of the inhibition of the RA-dependent induction of tTG is still unknown.…”

Section: Discussionmentioning

confidence: 99%

Induction of apoptosis by all-trans retinoic acid in the human myeloma cell line RPMI 8226 and negative regulation of some of its typical morphological features by dexamethasone

et al. 1999

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We investigated the effects of all-trans retinoic acid (RA) and dexamethasone (Dex) on the in vitro growth of the human myeloma cell line RPMI 8226. RA inhibited RPMI 8226 cell growth by both antiproliferative effect and induction of apoptosis. Typical morphological and biochemical characteristics of apoptosis including chromatin condensation, apoptotic bodies formation and internucleosomal DNA cleavage were detected after 4 days of treatment with 1 mM RA. In situ TUNEL assay demonstrated that DNA cleavage preceded chromatin condensation. The expression of tissue transglutaminase (tTG), an enzyme proposed to play a role in apoptosis was induced with RA, as shown by both enzymatic assay and in situ immunofluorescence detection. Dex, when used alone, had no effect on cell growth and apoptosis. When combined to RA, Dex did not interfere with the RA-dependent inhibition of cell proliferation, but unexpectedly inhibited both quantitatively and qualitatively several morphological and biochemical features of the apoptosis induced by RA. Dex did not affect RA-induced DNA breaks formation but impeded the progression of chromatin condensation and the formation of apoptotic bodies. Interestingly, Dex also inhibited the RAdependent induction of tTG. RU486, a glucocorticoid antagonist, counteracted all Dex effects. Taken together these data demonstrate that key cytoplasmic and nuclear events occurring during apoptosis are differentially regulated by RA and Dex in myeloma cell line RPMI 8226.

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Design and Synthesis of Potent Retinoid X Receptor Selective Ligands That Induce Apoptosis in Leukemia Cells

Cited by 315 publications

References 28 publications

The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice

The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice

Methylation of the retinoid response gene TIG1 in prostate cancer correlates with methylation of the retinoic acid receptor beta gene

Induction of apoptosis by all-trans retinoic acid in the human myeloma cell line RPMI 8226 and negative regulation of some of its typical morphological features by dexamethasone

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